Biology subjects

Doser, R. L.

Publications and source records attributed to Doser, R. L..

6 recordsLinked to original sources

bioRxiv2026

Activity-Dependent Postsynaptic Mitochondrial ROS Signaling Drives Avoidance Plasticity in C. elegans

Reactive oxygen species (ROS) are signaling molecules involved in neuronal excitatory function, with mitochondrial ROS (mitoROS) playing key roles in metabolic regulation and stress responses. Studies have shown that neuronal activity upregulates mitoROS production through oxidative phosphorylation, but it remains unclear if and how acute elevations in mitoROS influence synaptic plasticity. Here, we develop an avoidance sensitization paradigm in C. elegans using optogenetic excitation and training of nociceptive ASH neurons to initiate avoidance reversals by downstream activation of the AVA command interneurons. Using this paradigm, we show that the probability of reversal to light stimulation increases 4-hours after optogenetic training, indicating behavioral sensitization. This avoidance sensitization is accompanied by an increase of surface glutamate receptor (GLR-1) levels at ASH-AVA synapses which is dependent on postsynaptic expression of GLR-1 and active transcription. Interestingly, we find that somatic and nerve ring mitochondria produce ROS after optogenetic training. We show that this mitochondrial ROS (mitoROS) peak is dependent on postsynaptic GLR-1 and MCU-1 function during optogenetic training and is necessary for avoidance sensitization. Finally, we demonstrate that postsynaptic signaling by mitoROS in AVA is sufficient to induce avoidance sensitization. Postsynaptic photoactivation of mitochondria-targeted Killer Red in AVA, calibrated to produce the mitoROS peak observed during training, induces avoidance sensitization bypassing optogenetic training and MCU-1 requirement. Our results indicate that activity-dependent mitoROS signaling can instruct synaptic strengthening and directly modulate circuit function and behavior. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/730457v2_ufig1.gif" ALT="Figure 1"> View larger version (113K): org.highwire.dtl.DTLVardef@91f9bborg.highwire.dtl.DTLVardef@1a274b1org.highwire.dtl.DTLVardef@9b394forg.highwire.dtl.DTLVardef@cf8b7d_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

Mitochondrial double-stranded RNA accumulation in brain aging and Alzheimer's disease

Mitochondria and inflammation are tightly linked in aging and Alzheimers disease (AD), and recent evidence implicates mitochondrial double-stranded RNA (mt-dsRNA) as a potential trigger of inflammation. We examined mt-dsRNA accumulation and dsRNA signaling in brain aging and AD using human brain tissue and complementary in vitro transcriptomic datasets, quantifying mitochondrial transcripts and dsRNA editing. We found that mt-dsRNA accumulated after midlife and coincided with reduced expression of mitochondrial RNA processing and translation machinery, along with increased expression of dsRNA antiviral signaling proteins, consistent with cytoplasmic mt-dsRNA-driven inflammation. In AD brains, mt-dsRNA accumulation was further increased and correlated with cognitive impairment, neuropathological severity, and AD risk genotypes. Genes associated with these measures reflected altered ubiquitin-dependent regulation of antiviral signaling, potentially indicating altered sensitivity to mt-dsRNA. Together, these findings highlight mitochondrial RNA homeostasis as an unrecognized contributor to age- and AD-related neurodegeneration by identifying mt-dsRNA as a potential driver of chronic inflammation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/703345v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@81f384org.highwire.dtl.DTLVardef@19a8138org.highwire.dtl.DTLVardef@99b597org.highwire.dtl.DTLVardef@1610120_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Activity-dependent Mitochondrial ROS Signaling Regulates Recruitment of Glutamate Receptors to Synapses

Our understanding of mitochondrial signaling in the nervous system has been limited by the technical challenge of analyzing mitochondrial function in vivo. In the transparent genetic model Caenorhabditis elegans, we were able to manipulate and measure mitochondrial signaling as well as neuronal activity in vivo. Using this approach, we provide evidence supporting a novel role for mitochondrial signaling in dendrites. Specifically, we show that dendritic mitochondria take up calcium (Ca2+) via the mitochondrial Ca2+ uniporter MCU-1 causing an upregulation of mitochondrial reactive oxygen species (mitoROS) production. We also observed that mitochondria are positioned in close proximity to synaptic clusters of GLR-1, the C. elegans ortholog of the AMPA subtype of glutamate receptors that mediate neuronal excitation. We show that synaptic recruitment of GLR-1 is downregulated by mitoROS signaling resulting from mitochondrial Ca2+ uptake via MCU-1. Thus, postsynaptic mitochondria provide a means of negative feedback that regulates excitatory synapse function which may be vital for neuronal homeostasis by preventing excitotoxicity and energy depletion.

neuroscience↗

bioRxiv2022

A Dual Role for LAR-RPTP in Regulating Long-distance Transport and Synaptic Retention of AMPARs, Essential for Long Term Associative Memory

The AMPA subtype of ionotropic glutamate receptors (AMPARs) plays an essential role in excitatory synaptic transmission, learning, and memory. The majority of AMPARs are made in the cell body and are transported by molecular motors to synapses. Maintaining the proper number of synaptic receptors requires coordinated regulation of receptor production, export from the soma and delivery at synapses. This major logistical process is essential for circuit function and behavior. Although recent studies have shown that long-distance synaptic transport is regulated by neuronal activity, little is known about the mechanisms that coordinate somatic export or synaptic delivery and removal. Here we show that loss of the PTP-3A isoform of the receptor tyrosine phosphatase PTP-3 (the C. elegans homologue of vertebrate LAR-RPTP) leads to a [~]60% decrease in AMPAR transport; this affects synaptic delivery of AMPARs and synaptic functions necessary for long-term associative olfactory memory in C. elegans. Interestingly, while complete loss of PTP-3A leads to defects in transport and local synaptic trafficking of AMPARs, loss of only PTP-3 phosphatase function affects local synaptic recycling and retention of AMPARs. Finally, we show that the N-terminus of PTP-3A regulates transport, whereas the C-terminal regulates synaptic retention of AMPARs. Altogether, our results suggest a model in which the two domains of PTP-3/LAR-RPTPs have specific, complementary roles in coordinating somatic export and local retention of AMPARs essential for long-term associative memory.

neuroscience↗

bioRxiv2022

Surface Acoustic Wave Integrated Microfluidics for Repetitive and Reversible Temporary Immobilization of C. elegans

Caenorhabditis elegans is an important genetic model for neuroscience studies due to its unique combination of genetics, transparency, complete synaptic connectome, and well-characterized behaviors. These factors, in turn, enable analyses of how genes control connectivity, neuronal function, and behavior. To date, however, most studies of neuronal function in C. elegans are incapable of performing microscopy imaging with subcellular resolution and behavior analysis in the same set of animals. This constraint stems from the immobilization requirement for high-resolution imaging that is incompatible with behavioral analysis. In particular, conventional immobilization methods often lead to either irreversible, partial, or slowly reversible immobilization of animals preventing a multiplexed approach. Here, we present a novel microfluidic device that uses surface acoustic waves (SAW) as a non-contact method to temporarily immobilize worms for a short period (40 seconds). This device allows non-invasive analysis of swimming behavior and high-resolution synaptic imaging in the same animal. In addition, because of the low impact of this SAW approach, the device enables fast, repeated imaging of single neurons and behavior in the same animals for three to four days. We anticipate that this device will enable longitudinal analysis of animal motility and subcellular morphological changes during development and ageing in C. elegans.

neuroscience↗

bioRxiv2020

Reactive Oxygen Species Modulate Activity-Dependent AMPA Receptor Transport in C. elegans

The AMPA subtype of synaptic glutamate receptors (AMPARs) play an essential role in cognition. Their function, numbers and change at synapses during synaptic plasticity, is tightly regulated by neuronal activity. Although we know that long-distance transport of AMPARs is essential for this regulation, we dont understand the regulatory mechanisms of it. Neuronal transmission is a metabolically demanding process in which ATP consumption and production are tightly coupled and regulated. Aerobic ATP synthesis unavoidably produces reactive oxygen species (ROS), such as hydrogen peroxide, which are known modulators of calcium signaling. Although a role for calcium signaling in AMPAR transport has been described, there is little understanding of the mechanisms involved and no known link to physiological ROS signaling. Here, using real-time in vivo imaging of AMPAR transport in the intact C. elegans nervous system, we demonstrate that long-distance synaptic AMPAR transport is bidirectionally regulated by calcium influx and activation of calcium/calmodulin-dependent protein kinase II. Quantifying in vivo calcium dynamics revealed that modest, physiological increases in ROS decrease calcium transients in C. elegans glutamatergic neurons. By combining genetic and pharmacological manipulation of ROS levels and calcium influx, we reveal a mechanism in which physiological increases in ROS cause a decrease in synaptic AMPAR transport and delivery by modulating activity-dependent calcium signaling. Taken together, our results identify a novel role for oxidant signaling in the regulation of synaptic AMPAR transport and delivery, which in turn could be critical for coupling the metabolic demands of neuronal activity with excitatory neurotransmission. SIGNIFICANCE AND IMPACTSynaptic AMPARs are critical for excitatory synaptic transmission. The disruption of their synaptic localization and numbers is associated with numerous psychiatric, neurological, and neurodegenerative conditions. However, very little is known about the regulatory mechanisms controlling transport and delivery of AMPAR to synapses. Here, we describe a novel physiological signaling mechanism in which ROS, such as hydrogen peroxide, modulate AMPAR transport by modifying activity-dependent calcium influx. Our findings provide the first evidence in support of a mechanistic link between physiological ROS signaling, AMPAR transport, localization, and excitatory transmission. Of potential therapeutic importance, dysregulation of intracellular calcium and ROS signaling is implicated in the pathogenesis of several neurodegenerative disorders including Alzheimers and Parkinsons disease.

neuroscience↗